The functioning of neuronal circuits in the cerebral cortex underlies our highest cognitive and perceptual abilities, yet the rules underlying the formation of specific connections among cortical neurons are largely unknown. During development, proliferating cells of the cortical neuroepithelium generate young neurons that migrate away from their site of origin into distinct positions within the cortex, where they assemble into the layers and columns that form the structural basis of cortical processing. Defects in the production and migration of cerebral cortical neurons have fundamental implications for mental health, particularly since migration disorders have been implicated in schizophrenia and bipolar affective illness. The goal of this research is to explore the cellular and molecular processes by which neural progenitor cells in the mammalian cerebral cortex produce young neurons, and to study how these neurons migrate to appropriate positions within the brain. Five specific issues are under study: 1) Which cytoskeletal elements support interkinetic nuclear migration during the cell cycle? We will first characterize the cytoskeletal elements that underlie this intracellular movement, then test the effects of disrupting nuclear movements on the ability of cells to make phenotypic commitments. 2) What are the patterns of cell division that produce young cortical neurons? We propose to image directly patterns of cell division in the ventricular zone using time-lapse confocal microscopy to determine whether cell divisions are symmetric or asymmetric. 3) What are the pathways for neuronal migration in the developing cerebral cortex? Time-lapse imaging techniques will be used to characterize the diversity of migratory pathways in slices through the developing cortex. 4) What are the cellular substrates for migration in the radial and orthogonal (tangential) domains? We will explore a range of possible substrates for both radial and nonradical migration, using electron microscopy and immunohistochemical techniques. 5) What molecules are required for migratory movements in the radial and orthogonal domains? We will characterize the molecular basis of neuronal migration in the radial and orthogonal domains through the use of function-blocking antibodies (to molecules such as Beta1-integrin, L1, and NCAM) and time-lapse imaging techniques. The results of these experiments will provide us with information about the cellular and molecular mechanisms of neurogenesis and neuronal migration in the developing cerebral cortex. Such studies of normal development are likely to provide important insights into the ontogeny of developmental brain disorders in human, and ultimately to generate strategies for the appropriate treatment of such disorders.